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GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons.
Molecular Psychiatry ( IF 11.0 ) Pub Date : 2017-07-11 , DOI: 10.1038/mp.2017.137
N Benamer 1 , F Marti 1 , R Lujan 2 , R Hepp 1 , T G Aubier 1 , A A M Dupin 1 , G Frébourg 3 , S Pons 4, 5 , U Maskos 4, 5 , P Faure 1 , Y A Hay 1 , B Lambolez 1 , L Tricoire 1
Affiliation  

Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia.

中文翻译:

与精神分裂症相关的GluD1控制多巴胺神经元的爆发放电。

编码孤儿delta1谷氨酸受体通道(GluD1)的GRID1基因的人类突变与精神分裂症有关,但尚不清楚GluD1在脑回路中的明确作用。基于其旁系同源物GluD2在小脑中的已知功能,我们寻找GluD1在中脑多巴胺神经元的代谢型受体mGlu1介导的慢谷氨酸能传递中的作用,该神经元的功能障碍是精神分裂症的标志。我们发现,mGlu1激动剂在共表达mGlu1和GluD1的HEK细胞中引起缓慢的去极化电流,但在单独表达mGlu1或GluD1的细胞中不引起去极化电流。显性阴性GluD1死孔突变体的其他共表达消除了该电流。然后,我们从中脑切片中表征了多巴胺神经元中mGlu1依赖的电流。激动剂诱发的和缓慢的突触后电流都通过显性负性GluD1突变体的表达而被消除,表明天然GluD1通道参与了这些电流。同样,这两个mGlu1依赖电流在GRID1基因敲除小鼠中均受到抑制,据报道该小鼠表现出与精神分裂症有关的内表型。众所周知,mGlu1激活会触发多巴胺神经元从强直性放电到猝发放电的转变,这会发出明显的刺激信号并编码奖励预测。多巴胺神经元的体内记录表明,在GRID1基因敲除小鼠中或在野生型小鼠中靶定显性阴性GluD1突变体的靶向表达后,它们的自发爆发放电被取消。我们的结果取消了对GluD1的孤立化,
更新日期:2018-02-21
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